POS0197 SARS-CoV-2 INFECTION CAUSED THROMBOSIS IN THE LUPUS MODEL WITH ANTIPHOSPHOLIPID ANTIBODY, WHEREAS COVID-19 ASSOCIATED THROMBOSIS WAS IRRELEVANT IN PATIENTS WITH POSITIVE ANTIPHOSPHOLIPID ANTIBODY
Authors: S. Oba, T. Hosoya, D. Kawata, W. Lee, M. Kamiya, Y. Komiya, H. Iwai, Y. Nukui, S. Tohda, S. Yasuda
Journal: Annals of the Rheumatic Diseases (2022)

Background Thrombosis is a unique complication in coronavirus disease 2019 (COVID-19). We have reported that elevated ferritin and D-dimer on admission were the risk factors of thromboses by analyzing the patients sequentially admitted to our hospital due to COVID-19 (1). However, we have not analyzed thrombotic complications in the view of the antiphospholipid antibodies (aPLs), which are frequently detected in the COVID-19 patients. Objectives To elucidate the thrombogenic effects of aPLs in COVID-19, we analyzed the development of thrombosis in three lupus models after SARS-CoV-2 infection. Additionally, we evaluated the association of thrombotic events and the serum profile of aPLs in Japanese patients with COVID-19. Methods Three animal models of lupus (MRL- lpr/lpr , NZBxNZW F1 and NZW×BXSB F1) were evaluated in this study. NZW×BXSB F1 was also considered as a model of antiphospholipid syndrome (APS) since aPLs were detected with a high titer (2). Experimental SARS-CoV-2 infection was induced using mouse-passaged virus strain (3). The incidence of thromboses in the lungs and kidneys were identified by evaluating H&amp;E staining and PTAH staining of paraffin-embedded sections. We have experienced 44 thrombotic events in 34 out of 594 patients admitted to our institute. As a non-thrombotic COVID-19, 68 patients were selected to make a 1 to 2 matched-pair based on the propensity score. In total 102 patients, seven types of aPLs (anti-cardiolipin (CL) IgG/IgM, anti-β2GP1 IgG/IgA/IgM, and anti-phosphatidyl serine/prothrombin complex (PS/PT) IgG/IgM) were measured using specific ELISA kits. The patients’ clinical characteristics and serological profile of aPLs were further evaluated. Results We identified the development of thromboses in the lungs or kidneys in 6 out of 12 (50%) NZW×BXSB F1 mice after the SARS-CoV-2 infection, whereas no thrombosis was observed in non-infected mice. Further, there was no thrombosis in the other lupus models (0%) after the infection. These findings might suggest the pathogenic role of aPLs under the SARS-CoV-2 infection. Among our COVID-19 patients, 39 out of 102 (38%) were tested positive for one or more aPLs. The positive ratios of any aPLs were statistically indifferent between the patients with or without thrombosis; anti-CL IgG (8.8% vs 5.9%)/IgM (0% vs 5.9%), anti-β2GP1 IgG (21% vs 12%)/IgA (8.8% vs 15%)/IgM (0% vs 1.5%), and anti-PS/PT IgG (0% vs 2.9%)/IgM (12% vs 13%), respectively. In addition, their titers were relatively lower than those observed in APS patients. The patients’ characteristics and the prognosis of COVID-19 were comparable regardless of the detection of any aPLs. These findings suggested that COVID-19 associated aPLs were irrelevant to thrombotic complications. Conclusion Thromboses were induced after the infection of SARS-CoV-2 only in the APS model. However, aPLs detected in COVID-19 patients have little impact on the development of thrombosis. SARS-CoV-2 infection might have a high risk of thrombosis, especially in APS patients, as shown in the case report (4). The discrepancy of its thrombogenic effects of aPLs might be explained by the low titer of the antibody or the diversity of antibody epitope. Further analyses are required to clarify the mechanisms of aPLs production and the development of thrombosis in COVID-19. References [1]Oba S, et al. Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single-Center Analysis in Japan. Front Cardiovasc Med. 2021 Nov 19;8:767074. [2]Hashimoto Y, et al. Anticardiolipin antibodies in NZW x BXSB F1 mice. A model of antiphospholipid syndrome. J Immunol. 1992 Aug 1;149(3):1063-8. [3]Iwata-Yoshikawa N, et al. A lethal mouse model for evaluating vaccine-associated enhanced respiratory disease during SARS-CoV-2 infection. Sci Adv. 2022 Jan 7;8(1):eabh3827. [4]Chidharla A, et al. A Case Report of COVID-Associated Catastrophic Antiphospholipid Syndrome Successfully Treated with Eculizumab. J Blood Med. 2021 Oct 30;12:929-933. Disclosure of Interests Seiya Oba: None declared, Tadashi Hosoya Speakers bureau: Janssen Pharmaceutical K.K. Daiichi Sankyo Company, limited Asahi Kasei Corporation Ono pharmaceuticals Eisai Eli Lilly, Daisuke Kawata: None declared, Wenshi Lee: None declared, Mari Kamiya: None declared, Yoji Komiya: None declared, Hideyuki Iwai: None declared, Yuko Nukui: None declared, Shuji Tohda: None declared, Shinsuke Yasuda Speakers bureau: Abbvie, Asahi Kasei Pharma, Chugai Pharmaceutical, Eisai, Eli Lilly, GlaxoSmithKline, Mitsubishi Tanabe Pharma, Ono pharmaceutical, Pfizer., Consultant of: ImmunoForge, Grant/research support from: Abbvie, Asahi Kasei Pharma, Chugai Pharmaceutical, CSL Behring, Eisai, ImmunoForge, Mitsubishi Tanabe Pharma, Ono pharmaceutical